Aqueous suspension with good redispersibility

ABSTRACT

The aqueous suspension can be prepared by incorporating, in an aqueous suspension of a hardly soluble drug, a water-soluble polymer within the concentration range from the concentration at which the surface tension of the aqueous suspension of the drug begins to decrease up to the concentration at which the reduction in surface tension ceases. The resulting aqueous suspension shows ready redispersibility and will not undergo aggregation of dispersed particles or caking. Because of its good redispersibility, the suspension is useful as a parenteral preparation, eye drops, nasal drops, a preparation for oral administration, a lotion or the like.

TECHNICAL FIELD

[0001] The present invention relates to an aqueous suspension with goodredispersibility.

BACKGROUND ART

[0002] In preparing, for instance, an ophthalmic preparation, nasalpreparation or parenteral preparation containing a medicinal compoundhardly soluble in water, it is presumable that the drug be suspended inan aqueous medium to give an aqueous suspension. When such aqueoussuspension is stored for a long period, the drug occurring as dispersedparticles (hereinafter sometimes referred to merely as dispersedparticles) tends to undergo aggregation, resulting in increases in sizeof dispersed particles or sedimentation of dispersed particles andfurther in secondary aggregation of the dispersed particles that havesettled, for example caking. Therefore, efforts have been devoted toprevent the aggregation or sedimentation of dispersed particles as faras possible or, when such aggregation or sedimentation cannot beprevented, to obtain suspensions capable of readily regaining theiroriginal state.

[0003] One method so far proposed comprises making dispersed particlessmaller, decreasing the difference between the specific gravity ofdispersed particles with of the dispersion medium and increasing theviscosity of the dispersion medium to thereby prevent the particles fromsettling. In such cases, for increasing the viscosity of the dispersionmedium, the concentration of the suspending agent and/or thickeningagent, such as a water-soluble polymer, has generally been selectedwithin the range of 0.2 to 5.0% (w/v: weight/volume).

[0004] However, even when the concentration of the suspending agentand/or thickening agent is within such range, the sedimentation ofparticles cannot entirely be prevented. The problem which remains isthat dispersed particles settle and deposit, causing caking, resultingin failure of uniform redispersion.

[0005] Another method which is conceivable comprises making drugparticles greater in size to thereby improve their redispersibility. Inthe case of an ophthalmic preparation, however, greater particle sizesmay cause a foreign matter sensation or eye irritation uponinstillation. In the case of a nasal preparation, greater particle sizesmake it impossible to apply it from a spray bottle. In the case of aninjection, it is a drawback that it cannot be administered through aneedle.

DISCLOSURE OF INVENTION

[0006] Among the drugs recently developed and producing pharmacologicaleffects of value, many are hardly soluble ones. For supplying these inthe form of aqueous preparations such as ophthalmic, nasal, parenteraland other preparations, it is unavoidable in many instances to employthe aqueous suspension form. However, the prior art aqueous suspensionshave a redispersibility problem; in many instances, it is difficult torestore suspensions uniform in concentration without a long time ofshaking to effect redispersion. Thus, the advent of aqueous drugsuspensions which can be readily prepared and have good redispersibilityhas been waited for. Accordingly, it is the primary object of thepresent invention to provide an aqueous suspension showing goodredispersibility without undergoing aggregation of dispersed particlesor caking.

[0007] The present inventors made intensive investigations to solve theabove problems and, as a result, found that there is a certainrelationship between the surface tension of an aqueous suspension andthe redispersibility thereof. Based on such finding, they have nowcompleted the present invention.

[0008] The invention is thus concerned with an aqueous suspensioncomprising a hardly soluble drug together with a water-soluble polymerwithin the concentration range from the concentration at which thesurface tension of the drug suspension begins to decrease up to theconcentration at which the reduction in surface tension ceases.

[0009] As will be shown later herein in Test Example 1, the surfacetension of an aqueous suspension begins to decrease with the increase inthe amount of a water-soluble polymer added thereto. Upon continuationof the addition, the reduction in surface tension ceases and,thereafter, a substantially constant surface tension is maintained. Onthe contrary, the redispersibility of the dispersed particles of anaqueous suspension becomes good at the point at which the surfacetension of the aqueous suspension begins to decrease as a result ofaddition of the water-soluble polymer, and the good redispersibility ismaintained until the reduction in surface tension ceases. Thereafter, asthe reduction in surface tension ceases and the surface tension becomesconstant, the redispersibility of the dispersed particles becomesgradually worsened.

[0010] Where no water-soluble polymer is present, the dispersedparticles aggregate together and float on the surface of the suspensionand therefore no uniform suspension can be prepared.

[0011] The concentration of a water-soluble polymer at which the surfacetension of an aqueous drug suspension begins to decrease and theconcentration of the water-soluble polymer at which the reduction insurface tension ceases generally increase according to the contents ofthe hardly soluble drug used in the aqueous suspension but varydepending on the physical properties, chemical structure, andconcentration and particle size of the hardly soluble drug, amongothers. The water-soluble polymer concentration at which the surfacetension of the drug suspension begins to decrease is generally 0.00001to 0.01% (w/v), preferably 0.00005 to 0.005% (w/v), while thewater-soluble polymer concentration at which the reduction in surfacetension of the suspension ceases is generally 0.0001 to 0.1% (w/v),preferably 0.001 to 0.01% (w/v).

[0012] The aqueous suspension of the present invention is generallyprepared at a water-soluble polymer concentration within the range of0.00001 to 0.1% (w/v), preferably 0.00005 to 0.05% (w/v), morepreferably 0.0001 to 0.01 w/v %.

[0013] The ratio of the water-soluble polymer to the hardly soluble drugis generally 0.0001 to 0.2 part by weight, preferably 0.0005 to 0.1 partby weight, more preferably 0.0005 to 0.05 part by weight of the formerto 1 part by weight of the latter.

[0014] The water-soluble polymer to be used in the practice of thepresent invention may be any pharmaceutically acceptable water-solublepolymer, irrespective of type or category. Cellulose derivatives andwater-soluble polyvinyl polymers are suited for use, however.

[0015] As the cellulose derivatives, there may be mentioned, forexample, hydroxypropylmethylcellulose, methylcellulose,hydroxyethylcellulose and hydroxypropylcellulose. Particularly preferredamong them are hydroxypropylmethylcellulose and methylcellulose.

[0016] As the water-soluble polyvinyl polymers, there may be mentioned,among others, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30,polyvinylpyrrolidone K90, and polyvinyl alcohol (partial hydrolyzedproduct, complete hydrolyzed product).

[0017] As used herein, the “hardly soluble drug” includes, within themeaning thereof, those drugs which belong, in solubility classification,to one of the groups “sparingly soluble”, “slightly soluble”, “veryslightly soluble” and “practically insoluble” as so defined in theJapanese Pharmacopoeia. Thus, it includes all drugs that can be providedin the final dosage form of aqueous suspensions.

[0018] As specific examples of the hardly soluble drug to be used in thepractice of the present invention, there may be mentioned steroidalantiinflammatory agents, antiinflammatory analgesics, chemotherapeuticagents, synthetic antibacterial agents, antiviral agents, hormones,anticataract agents, neovascularization inhibitors, immunosuppressants,protease inhibitors, and aldose reductase inhibitors, among others. Thesteroidal antiinflammatory agents include, among others, cortisoneacetate, hydrocortisone acetate, betamethasone, prednisolone,fluticasone propionate, dexamethasone, triamcinolone, loteprednol,fluorometholone, difluprednate, momethasone furoate, clobetasolpropionate, diflorasone diacetate, diflucortolone valerate,fluocinonide, amcinonide, halcinonide, fluocinolone acetonide,triamcinolone acetonide, flumetasone pivalate and clobetasone butyrate.The antiinflammatory analgesics include, among others, alclofenac,aluminopropfen, ibuprofen, indomethacin, epirizole, oxaprozin,ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam,fenbufen, flutenamic acid, flurbiprofen, floctafenine, pentazocine,metiazinic acid, mefenamic acid and mofezolac. The chemotherapeuticagents include, among others, sulfa drugs such as salazusulfapyridine,sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazineand sulfamonomethoxine, synthetic antibacterial agents such as enoxacin,ofloxacin, cinoxacin, sparfloxacin, thiamphenicol, nalidixic acid,tosufloxacin tosilate, norfloxacin, pipemidic acid trihydrate, piromidicacid, fleroxacin and levofloxacin, antiviral agents such as aciclovir,ganciclovir, didanosine, didovudine and vidarabine, and antifungalagents such as itraconazole, ketoconazole, fluconazole, flucytosine,miconazole and pimaricin. The hormones include, among others, insulinzinc, testosterone propionate and estradiol benzoate. The anticataractagents include, among others, pirenoxine and the like. Theneovascularization inhibitors include, among others, fumagillin andderivatives thereof. The immunosuppressants include, among others,ciclosporin, rapamycin and tacrolimus. The protease inhibitors include,among others, [L-3-trans-ethoxycarbonyloxiran-2-carbonyl]-L-leucine(3-methylbutyl)amide (E-64-d) and the like. The aldose reductaseinhibitors include, among others,5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione and the like.

[0019] The concentration of the hardly soluble drug to be used in thepractice of the invention may vary according to the drug species,indication, dosage and other factors. Generally, however, it is 0.01 to10.0% (w/v), preferably 0.1 to 5.0% (w/v).

[0020] The aqueous suspension of the present invention may contain, inaddition to the hardly soluble drug and water-soluble polymer, knowncompounds such as a buffer (e.g. carbonate salt, phosphate salt, acetatesalt, glutamic acid, citrate salt, ε-aminocaproic acid), an isotonizingagent (e.g. glycerol, mannitol, sorbitol, propylene glycol, sodiumchloride, potassium chloride, boric acid), a stabilizer (e.g. sodiumedetate, sodium citrate), a surfactant (e.g. polysorbate 80,polyoxyethylene(60) hydrogenated castor oil, tyloxapol, benzalkoniumchloride), a preservative (p-hydroxybenzoate and it's analogs,benzalkonium chloride, benzethonium chloride, chlorobutanol), a pHcontrol agent (e.g. hydrochloric acid, sodium hydroxide, phosphoricacid), and other additives.

[0021] In cases where an additive which may influence the surfacetension of the aqueous suspension, for example a surfactant, is used, itis preferred that the surface tension measurement be made prior toaddition of the surfactant and the surfactant be added after selectionof the concentration of the water-soluble polymer.

[0022] The pH of the aqueous suspension of the present invention is notcritical but, generally, it is 4 to 9, preferably 5 to 8. It ispreferred that the surface tension be selected according to the intendedpH of the aqueous suspension.

[0023] The aqueous suspension of the invention has good redispersibilitywithout involving aggregation or caking of dispersed particles and,therefore, can be used with advantage as, for example, an ophthalmicpreparation, a preparation for nasal application, an injection, apreparation for oral administration or a lotion.

BRIEF DESCRIPTION OF DRAWINGS

[0024]FIG. 1 is a graphic representation of the relationships betweenthe HPMC concentration and the surface tension and redispersion time fora 0.1% (w/v) fluorometholone suspension as found in Test Example 1. Inthe figure, -- indicates the surface tension, and -♦- indicates theredispersion time.

BEST MODE FOR CARRYING OUT THE INVENTION

[0025] The following test examples and working examples illustrate theinvention in further detail. They are, however, by no means limitativeof the scope of the invention.

Test Example 1 Surface Tension-Redispersibility Test

[0026] [Method]

[0027] Solutions containing a suspending agent in concentrations rangingfrom 0.000001 to 0.5 w/v % were first prepared. A test drug was added tothe solutions to prepare aqueous suspensions. The surface tension ofeach aqueous suspension thus prepared was measured with the Du Noüytension meter K122 (Krüss). The suspensions were then filled into 5 mlcolorless polypropylene bottles and allowed to stand at 25° C. for 4days. Each bottle was caused to spin (60 rpm) on the variable mix rotorVMR-5 (60 rpm, manufactured by Iuchi) and the time required forredispersion was measured. In addition, the condition of the redispersedparticles was visually examined.

[0028] As the suspending agent, hydroxypropylmethyl cellulose [Metolose60SH (TC-5E); manufactured by Shin-Etsu Chemical Co., Ltd.; hereinafterabbreviated as HPMC], methylcellulose (Metolose SM-25; manufactured byShin-Etsu Chemical Co., Ltd.; abbreviated as MC), orpolyvinylpyrrolidone (K30; manufactured by BASF; abbreviated as PVP) wasused. As the test drug, fluorometholone 0.05 w/v % or 0.1 w/v % orindomethacin 0.2 w/v % or 1.0 w/v % was used.

[0029] [Results]

[0030] (1) Relationship of the concentration of HPMC to the surfacetension and redispersion time of fluorometholone 0.1 w/v % suspension

[0031] The Relation Between the Surface Tension and Redispersibility ofa Fluorometholone 0.1 w/v % Suspension is shown in FIG. 1.

[0032] In the case of HPMC, the surface tension began to decline at0.0001 w/v % and the decrease in surface tension almost ceased at 0.01w/v. On the other hand, within the concentration range of 0.000005 to0.0001 w/v % HPMC, the time required for redispersion was 2 seconds butthe dispersed particles aggregated and floated, failing to give auniform suspension. Over the range of 0.0001 to 0.01 w/v % HPMC, theredispersion time was less than 4 seconds and a uniform suspension wasobtained without aggregation of suspended particles. When theconcentration of HPMC was over 0.01 w/v %, the redispersion timeexceeded 5 seconds, indicating that the redispersibility is adverselyaffected.

[0033] The preferred ratio of HPMC to fluorometholone was found to be0.001 to 0.1 part by weight of the former to 1 part by weight of thelatter.

[0034] (2) Relationship of the Concentration of HPMC to the SurfaceTension of Fluorometholone 0.05 w/v % Suspension

[0035] With HPMC, the surface tension began to decline at 0.0001 w/v %(surface tension: 65.1 mN/m) and the decrease in surface tension almostceased at 0.002 w/v % HPMC (surface tension: 50.5 mN/m). The timerequired for redispersion of fluorometholone in this concentration rangeof HPMC was about 6 seconds and the condition of the dispersion wassatisfactory.

[0036] The preferred ratio of HPMC to fluorometholone was 0.002 to 0.04part by weight of the former to 1 part by weight to the latter.

[0037] (3) Relationship of the Concentration of MC to the SurfaceTension and Redispersion Time of Fluorometholone 0.1 w/v % Suspension

[0038] With the concentration of MC being 0.0001 w/v % and below, thesurface-tension was almost constant at 72.5 mN/m. The surface tensionbegan to decline at 0.0001 w/v % MC and the decrease in surface tensionalmost ceased at 0.01 w/v %, when a tension value of 54.5 mN/m wasrecorded. On the other hand, when the concentration of MC was 0.0001 w/v% or less, the redispersion time was as short as 2 seconds or less butthe dispersed particles aggregated and floated, failing to give auniform suspension. Within the concentration range of 0.0001 to 0.01 w/v% MC, the necessary redispersion time was 9 to 10.7 seconds, withredispersion taking place rapidly without aggregation of dispersedparticles. When the concentration of MC was over 0.01 w/v %, theredispersion time was found to be close to 20 seconds, withredispersibility being adversely affected.

[0039] The preferred ratio of MC to fluorometholone was 0.001 to 0.1part by weight of the former to 1 part by weight of the latter.

[0040] (4) Relationship of the Concentration of HPMC to the SurfaceTension and Redispersion Time of Indomethacin 0.2 w/v % Suspension

[0041] When the concentration of HPMC was less than 0.0001 w/v %, thesurface tension was almost constant at 72 mN/m. The surface tensionbegan to decline at 0.0001 w/v % HPMC and the decrease in surfacetension almost ceased at 0.01 w/v % HPMC, with a tension value of 48mN/m being recorded. On the other hand, when the concentration of HPMCwas below 0.0001 w/v %, the redispersion time was as short as 7 secondsor less but the dispersed particles aggregated and floated, failing togive a uniform suspension. Within the concentration range of 0.0001 to0.01 w/v % HPMC, the redispersion time was 6.3 to 8.3 seconds, with thedrug being rapidly redispersed without aggregation. When theconcentration of HPMC was over 0.01 w/v %, the redispersibility wasfound to deteriorate, with the redispersion time exceeding 12 seconds.

[0042] The preferred ratio of HPMC to indomethacin was 0.0005 to 0.05part by weight of the former to 1 part by weight of the latter.

[0043] (5) Relationship of the Concentration of HPMC to the SurfaceTension and Redispersion Time of Indomethacin 1.0 w/v % Suspension

[0044] When the concentration of HPMC was below 0.0005 w/v %, thesurface tension was almost constant at 72.73 mN/m. The surface tensionbegan to decline at 0.0005 w/v % HPMC and the decrease in surfacetension almost ceased at 0.005 w/v %, at which level a tension value of49.7 mN/m was recorded. On the other hand, when the concentration ofHPMC was less than 0.0005 w/v %, the redispersion time was not more than7 seconds but the dispersed particles aggregated and floated, failing togive a uniform suspension. Within the concentration range of 0.0005 to0.005 w/v % HPMC, the redispersion time was 7.3 to 16 seconds, with thedrug particles being rapidly redispersed without aggregation. When theconcentration of HPMC exceeded 0.005 w/v %, the redispersion time wasincreased to more than 20 seconds, with the redispersibilitydeteriorating.

[0045] The preferred ratio of HPMC to indomethacin was 0.0005 to 0.005part by weight of the former to 1 part by weight of the latter.

[0046] (6) Relationship of the Concentration of PVP to the SurfaceTension of Fluorometholone 0.05 w/v % Suspension

[0047] The surface tension began to decline at 0.0902 w/v % PVC (surfacetension: 72.3 mN/m) and the decrease in surface tension almost ceased at0.001 w/v % (surface tension: 69.5 mN/m).

[0048] The preferred ratio of PVP to fluorometholone was 0.004 to 0.02part by weight of the former to 1 part by weight of the latter.

[0049] (7) Relationship of the Concentration of PVP to the SurfaceTension of Fluorometholone 0.1 w/v % Suspension

[0050] When the concentration of PVP was less than 0.0003 w/v %, thesurface tension was almost constant at 72.5 mN/m. The surface tensionbegan to decline at 0.0003 w/v % and the decrease in surface tensionalmost ceased at 0.002 w/v % where a tension value of 69.5 mN/m wasrecorded. The time necessary for redispersion of fluorometholone in thisconcentration range was about 6 seconds and the condition of thedispersion was satisfactory. When the concentration of PVP was in excessof 0.002 w/v %, the redispersion time was prolonged to 18 seconds orlonger, with the redispersibility being found to deteriorate.

[0051] The preferred ratio of PVP to indomethacin was 0.003 to 0.02 partby weight of the former to 1 part by weight of the latter.

[0052] The above results indicate that although the surface tension ofthe aqueous suspension is dependent on the kind of water-soluble polymeradded and the kind and concentration of hardly soluble drug, suspensionsof hardly soluble drugs with good redispersibility can be preparedwithin the concentration range of the water-soluble polymer from thelevel where the surface tension begins to decline to the level where thedecrease in surface tension ceases, regardless of the kind ofwater-soluble polymer.

TEST EXAMPLE 2

[0053] Redispersibility Test Under Accelerated Conditions

[0054] [Method]

[0055] Ophthalmic preparations were prepared according to Examples 2 and4 presented below and each preparation was filled in a 5 mlpolypropylene bottle. After the bottle was centrifuged at 200 G for 10minutes for forced sedimentation of the suspended particles, it wascaused to spin (60 rpm) on the variable mix rotor VMR-5 (60 rpm, Iuchi)and the redispersion time was measured.

[0056] [Results]

[0057] The redispersion times of the ophthalmic preparations of Examples2 and 4 were 4 seconds and 7 seconds, respectively. Gross observation ofeach redispersed suspension showed a uniform dispersion of fineparticles.

[0058] The above results indicate that in the case of the aqueoussuspension according to the invention, its redispersibility is wellmaintained even under the rugged condition of forced sedimentation ofthe particles by centrifugation and is not affected by the buffer andpreservative ingredients, either.

EXAMPLE 1 Ophthalmic Preparation

[0059] Fluorometholone 0.1 g Methylcellulose 0.0006 g Sodium chloride0.85 g Disodium hydrogenphosphate dodecahydrate 0.1 g Benzalkoniumchloride 0.005 g 0.1 N Hydrochloric acid q.s. to make pH 7.0 Purifiedwater q.s. to make 100 ml.

[0060] Methylcellulose was dissolved in about 80 ml of purified water byeffecting dispersion with warming, followed by cooling to roomtemperature. Sodium chloride, Disodium hydrogenphosphate dodecahydrateand benzalkonium chloride were added for dissolution. The pH wasadjusted to 7 by adding hydrochloric acid. Fluorometholone was added anduniform suspension was effected using a homogenizer. Purified water wasadded to make the whole volume 100 ml. A fluorometholone suspensionophthalmic preparation was thus prepared.

EXAMPLE 2 Ophthalmic Preparation

[0061] Fluorometholone 0.05 g Methylcellulose 0.0003 g Sodium chloride0.85 g Sodium dihydrogen phosphate dihydrate 0.1 g Benzalkonium chloride0.005 g 0.1 N Sodium hydroxide q.s. to make pH 7.0 Purified water q.s.to make 100 ml.

[0062] A fluorometholone suspension ophthalmic preparation was preparedin the same manner as in Example 1.

EXAMPLE 3 Ophthalmic Preparation

[0063] Fluorometholone 0.02 g Methylcellulose 0.0001 g Sodium chloride0.85 g Disodium hydrogenphosphate dodecahydrate 0.1 g Benzalkoniumchloride 0.005 g 0.1 N Hydrochloric acid q.s. to make pH 7.0 Purifiedwater q.s. to make 100 ml.

[0064] A fluorometholone suspension ophthalmic preparation was preparedin the same manner as in Example 1.

EXAMPLE 4 Ophthalmic Preparation

[0065] Fluorometholone 0.05 g Polyvinylpyrrolidone K30 0.0015 g Sodiumchloride 0.9 g Sodium dihydrogen phosphate dihydrate 0.1 g Benzalkoniumchloride 0.005 g 0.1 N Sodium hydroxide q.s. to make pH 7.0 Purifiedwater q.s. to make 100 ml.

[0066] Polyvinylpyrrolidone, sodium chloride, sodium dihydrogenphosphate dihydrate and benzalkonium chloride were added to about 80 mlof purified water and dissolution was effected. The pH was adjusted to 7by adding 0.1N sodium hydroxide. Fluorometholone was added and uniformsuspension was effected ultrasonically. The whole volume was made 100 mlby adding purified water. A fluorometholone suspension ophthalmicpreparation was thus prepared.

EXAMPLE 5 Ophthalmic Preparation

[0067] Sulfamonomethoxine 0.1 g Hydroxypropylmethylcellulose 0.001 gSodium acetate 0.1 g Benzalkonium chloride 0.005 g Sodium chloride 0.9 g0.1 N Hydrochloric acid q.s. to make pH 5.0 Purified water q.s. to make100 ml.

[0068] Hydroxypropylmethylcellulose was dissolved in about 80 ml ofpurified water by effecting dispersion with warming, followed by coolingto room temperature. Sodium chloride, sodium acetate and benzalkoniumchloride were added and dissolution was effected. The pH was adjusted to5 by adding hydrochloric acid. Sulfamonomethoxine was added and uniformsuspension was effected by means of a mill. The whole amount was made100 ml by adding purified water. A sulfamonomethoxine suspensionophthalmic preparation was thus prepared.

EXAMPLE 6 Nasal Drops

[0069] Hydrocortisone acetate 0.1 g Hydroxypropylmethylcellulose 0.0008g Sodium dihydrogen phosphate 0.1 g Methylparaben 0.026 g Propylparaben0.014 g Concentrated glycerin 2.6 g 0.1 N Sodium hydroxide q.s. to makepH 7.0 Purified water q.s. to make 100 ml.

[0070] Methylparaben and propylparaben were dissolved in about 80 ml ofpurified water with warming. Hydroxypropylmethylcellulose was dispersedin the warm solution for effecting dissolution, followed by cooling toroom temperature. Concentrated glycerin and sodium dihydrogen phosphatewere added and dissolution was effected. The pH was adjusted to 7 byadding sodium hydroxide. Hydrocortisone acetate was added and uniformsuspension was effected using a mixer. The whole volume was made 100 mlby adding purified water. A hydrocortisone acetate suspension for nasalapplication was thus prepared.

EXAMPLE 7 Parenteral Preparation (Injection)

[0071] Estradiol benzoate 5.0 g Hydroxypropylcellulose 0.03 gChlorobutanol 0.3 g Sodium chloride 0.9 g Purified water q.s. to make100 ml.

[0072] Chlorobutanol was dissolved in about 80 ml of purified water withwarming. Hydroxypropylcellulose was dissolved in the solution byeffecting dispersion with warming, followed by cooling to roomtemperature. Sodium chloride was added for dissolution, estradiolbenzoate was added, and uniform suspension was effected using ahomogenizer. The whole volume was made 100 ml by adding purified water.An estradiol benzoate suspension for parenteral administration was thusprepared.

EXAMPLE 8 Preparation for Oral Administration

[0073] Mefenamic acid 3.0 g Methylcellulose 0.01 g Sorbitol 20 g 5%Ethylparaben solution 1 ml Purified water q.s. to make 100 ml.

[0074] Methylcellulose was dissolved in about 50 ml of purified water byeffecting dispersion with warming, followed by cooling to roomtemperature. Sorbitol and 5% ethylparaben solution were added fordissolution. Mefenamic acid was added and uniform suspension waseffected using a homogenizer. The whole volume was made 100 ml by addingpurified water. A mefenamic acid suspension for oral administration wasthus prepared.

EXAMPLE 9 Lotion

[0075] Indomethacin 7.5 g Hydroxypropylcellulose 0.04 g dl-Camphor 0.5 gPurified water q.s. to make 100 ml.

[0076] Hydroxypropylcellulose was dissolved in about 50 ml of purifiedwater by effecting dispersion with warming, followed by cooling to roomtemperature. dl-Camphor was added for dissolution. Indomethacin wasadded and uniform suspension was effected ultrasonically. The wholevolume was made 100 ml by adding purified water. An indomethacinsuspension lotion was thus prepared.

INDUSTRIAL APPLICABILITY

[0077] The aqueous suspension of the present invention has goodredispersibility and therefore can be utilized as an excellent aqueoussuspension preparation, for example ophthalmic preparation, nasal drops,parenteral preparation, oral preparation, lotion or the like.

1. An aqueous suspension which comprises a hardly soluble drug togetherwith a water-soluble polymer within a concentration range from theconcentration at which the surface tension of the aqueous suspension ofsaid drug begins to decrease up to the concentration at which thereduction in surface tension ceases.
 2. The aqueous suspension of claim1, wherein the concentration of the water-soluble polymer at which thesurface tension of the aqueous drug suspension begins to decrease is0.00001 to 0.01% (w/v: weight/volume) and the concentration of thewater-soluble polymer at which the reduction in surface tension ceasesis 0.0001 to 0.1% (w/v).
 3. The aqueous suspension of claim 1, whereinthe concentration of the water-soluble polymer is within the range of0.00001 to 0.1% (w/v).
 4. The aqueous suspension of claim 1, wherein thewater-soluble polymer is a cellulose derivative or a water-solublepolyvinyl polymer.
 5. The aqueous suspension of claim 4 wherein thecellulose derivative is at least one member selected from the groupconsisting of hydroxypropylmethyl cellulose, methylcellulose,hydroxyethylcellulose and hydroxypropylcellulose.
 6. The aqueoussuspension of claim 4 wherein the water-soluble polyvinyl polymer is atleast one member selected from the group consisting ofpolyvinylpyrrolidone and polyvinyl alcohol.
 7. The aqueous suspension ofclaim 3 wherein the ratio of the water-soluble polymer to the hardlysoluble drug is 0.0001 to 0.2 part by weight of the former to 1 part byweight of the latter.
 8. The aqueous suspension of claim 1, saidsuspension being a topical ophthalmic preparation.
 9. The aqueoussuspension of claim 1, said suspension being a topical nasalpreparation.
 10. The aqueous suspension of claim 1, said suspensionbeing a parenteral preparation for injection.
 11. The aqueous suspensionof claim 1, said suspension being a preparation for oral administration.12. The aqueous suspension of claim 1, said suspension being a lotion.